1BWA

HIV-1 PROTEASE (V82F/I84V) DOUBLE MUTANT COMPLEXED WITH XV638 OF DUPONT PHARMACEUTICALS

Summary for 1BWA

• Entry DOI: 10.2210/pdb1bwa/pdb
• Descriptor: PROTEIN (HIV-1 PROTEASE), [4R-(4ALPHA,5ALPHA,6BETA,7BETA)]-3,3'-[[TETRAHYDRO-5,6-DIHYDROXY-2-OXO-4,7-BIS(PHENYLMETHYL)-1H-1,3-DIAZEPINE-1,3(2H)-D IYL] BIS(METHYLENE)]BIS[N-2-THIAZOLYLBENZAMIDE] (3 entities in total)
• Functional Keywords: hiv-1 protease, hydrolase
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor . Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585
• Total number of polymer chains: 2
• Total formula weight: 22406.40

Authors

Ala, P.,Chang, C.H. (deposition date: 1998-09-22, release date: 1998-10-30, Last modification date: 2024-02-07)

Primary citation

Ala, P.J.,Huston, E.E.,Klabe, R.M.,Jadhav, P.K.,Lam, P.Y.,Chang, C.H.
Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities.
Biochemistry, 37:15042-15049, 1998

PubMed Abstract: The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.

PubMed: 9790666
DOI: 10.1021/bi980386e

Experimental method

X-RAY DIFFRACTION (1.9 Å)